Association between redox dysregulation and vulnerability to cognitive deficits induced by maternal immune activation.

Abstract

Exposure to maternal immune activation (MIA) in utero is a major risk factor for neurodevelopmental disorders, including schizophrenia. However, a proportion of individuals are resilient to developing schizophrenia following exposure to MIA, which has also been reported in animal models of MIA. The molecular mechanisms leading to resilient and vulnerable behavioural phenotypes remain poorly understood, and we currently lack reliable blood biomarkers that predict resilience or vulnerability. Redox dysregulation, caused by an imbalance between oxidative stress and antioxidant defence mechanisms, has recently been predicted to be central to the pathogenesis of schizophrenia. Here, we use a poly(I:C)-induced MIA model of schizophrenia to investigate mechanisms underlying cognitive dysfunction and redox dysregulation in resilient and vulnerable individuals. We show that activity of the antioxidant enzyme superoxide dismutase (SOD) was reduced in the plasma of poly(I:C) offspring with a cognitive deficit, in contrast to individuals with typical cognition during both adolescence and adulthood. However, SOD activity in the hippocampus was not significantly different between vulnerable and resilient offspring. In addition, the lipid peroxidation marker malondialdehyde (MDA) and the pro-inflammatory cytokine IL-6 were not differentially expressed within the hippocampus or plasma of vulnerable poly(I:C) offspring. Our results suggest that reduced plasma SOD activity may be a potential blood biomarker to identify resilience or vulnerability to MIA-induced cognitive deficits. Further research is necessary to determine if reduced antioxidant capacity is present in plasma prior to symptom presentation and to understand if this predicts redox dysregulation in the brain.